Overcoming Chloroquine Resistance in Malaria: Design, Synthesis, and Structure-Activity Relationships of Novel Hybrid Compounds

Abstract

dResistance to antimalarial therapies, including artemisinin, has emerged as a significant challenge. Reversal of acquired resistance can be achieved using agents that resensitize resistant parasites to a previously efficacious therapy. Building on our initial work describing novel chemoreversal agents (CRAs) that resensitize resistant parasites to chloroquine (CQ), we herein report new hybrid single agents as an innovative strategy in the battle against resistant malaria. Synthetically linking a CRA scaffold to chloroquine produces hybrid compounds with restored potency toward a range of resistant malaria parasites. A preferred compound, compound 35, showed broad activity and good potency against seven strains resistant to chloroquine and artemisinin. Assessment of aqueous solubility, membrane permeability, and in vitro toxicity in a hepatocyte line and a cardiomyocyte line indicates that compound 35 has a good therapeutic window and favorable drug-like properties. This study provides initial support for CQ-CRA hybrid compounds as a potential treatment for resistant malaria.

Coupling the Antimalarial Cell Penetrating Peptide TP10 to Classical Antimalarial Drugs Primaquine and Chloroquine Produces Strongly Hemolytic Conjugates

“…The in vitro activity of Cq (4), which was the building block actually used in the synthesis of conjugates 5 and 10-14, was comparable to that of CQ (1); this was an expected observation, based on the well-known structure-activity relationships described for CQ and related compounds, which highlight the vital role of the 7-chloro-4-aminoquinoline core and the possibility to carry out slight to moderate changes in the aliphatic moiety without a major impact on activity [34]. Moreover, the equimolar mixture of Cq (4) with TP10 was also tested, but the apparent IC 50 value displayed, which was similar to that of Cq alone, cannot be regarded as an accurate one, as high standard deviation values were obtained.…”

Near Infrared Fluorophore-Tagged Chloroquine in Plasmodium falciparum Diagnostic Imaging

“…In this report, the squaraine dyes were coupled with chloroquine to serve as a malaria diagnostic probe, which is depicted in Scheme 2 . 5 was synthesized from known method [ 26 ] and reacted readily with Boc protected 6 [ 27 ] to give modified CQ 7 . By combining either SQR1 or SQR2 to CQ 7 , SQR1-CQ or SQR2-CQ were formed via amide bond coupling using HATU.…”

“…Compound 1 , 2 , 4 , 5 and 6 were prepared using previously reported literature methods [ 21 , 22 , 23 , 24 , 26 , 27 ].…”

Quinolines and Quinolones as Antibacterial, Antifungal, Anti-virulence, Antiviral and Anti-parasitic Agents

“…Unfortunately, malaria parasite has developed resistance to most of antimalarial drugs including CQ. Structural modifications of this chemotype, which would include altering the nature of the quinoline core and side chain at C(4)-position, or synthesis of organic (Boudhar et al 2016) or organo-metallic hybrids (Salas et al 2013) present a good direction for obtaining novel derivatives with better activity against CQ resistant strains (Manohar et al 2013).…”